A two-compartment model of the human retina

PURPOSE: In this article we question a basic concept in retinal pathology, which views the retina as composed primarily of neural elements, in a single compartment. METHODS: We suggest an alternative approach, centering on the epithelial-glial elements of the retina, dividing the retina into two distinct compartments. The framework of these two compartments is composed of two epithelial-like monostratified cell layers facing each other by their apical surfaces. This model is in agreement with the embryological development of the retina. RESULTS: Each compartment is composed of a monostratified cell layer in which neural elements are embedded and each is supplied by a different blood supply. The inner compartment, also referred to as the Muller cell compartment, extends between the inner and outer limiting membranes. The outer, or RPE, compartment extends between the outer limiting and Bruch's membranes. The border between the two compartments is formed by the outer limiting membrane (OLM). One simplified example utilizing the two-compartment concept is as follows: inner compartment edema (inner blood-retinal barrier breakdown) may manifest as cystoid edema, but not as serous retinal detachment, while outer compartment edema (outer blood-retinal barrier breakdown) may manifest as serous retinal detachment but not as cystoid edema, as long as the integrity of the OLM is maintained. CONCLUSION: A two-compartment approach to the structure of the retina, centering on non-neural elements, may enhance our understanding of some retinal pathologies. Various retinal diseases, mainly of vascular origin, are limited to one of the two compartments.     

New versatile physical model fitting the systemic circulation accurately

A physical model is developed for the simulation of the left heart and systemic circulation. The simulator includes a transparent and compliant ventricle pumping into an arterial model. The ability of the system to reproduce thein vivo conditions accurately is demonstrated by quantitative comjcarisons with physiological pressure and flow waveforms. As an example of application, flow patterns within the ventricle obtained by visualisation techniques and ultrasonic Doppler velocimetry are presented. Its versatility makes the system an essential tool in cardiovascular flow dynamics.     

Influence of transmural pressure on myogenic responses of isolated cerebral arteries of the rat

We examined the diameter responses of isolated and pressurized posterior cerebral artery branches to various static and dynamic pressure alterations. These vessels, dissected from an anatomically identifiable location in the rat brain, developed tone when placed in a normal calcium physiological salt solution (1.6 mM Ca-PSS). Following a series of transmural pressure steps (Δp) of 25 or 50 mm Hg completed in 1–2 s and made every 5 min, they attained additional tone resulting in a mean luminal diameter of 139 μm at 100 mm Hg which was 35% less than their relaxed size measured in 1 mM EGTA-PSS. Continuous measurements of wall thickness and lumen diameter were obtained using a video electronic system in 1–2 mm long arterial segments, and autoregulatory gain factors calculated. Myogenic responses were obtained from each of 6 vessels taken from 6 WKY rats. Diameters following the step pressure changes were usually stable within 2–4 min. The data defined a myogenic regulatory pressure range from 49–145 mm Hg. Gain values averaged about 17% of that necessary for these arteries to maintain perfect flow autoregulation. Our results for myogenicity are comparable with the pressure range for blood flow autoregulation reported by others for the rat. We conclude that myogenic mechanisms, at least in this size artery, are partly responsible for flow autoregulation, and that they are supplemented by metabolic mechanisms operative in the intact rat brain. Research supported by grant HL 17335 from the NHLBI.     

Development of a hydraulic model of the human systemic circulation

Physical and numeric models of the human circulation are constructed for a number of objectives, including studies and training in physiologic control, interpretation of clinical observations, and testing of prosthetic cardiovascular devices. For many of these purposes it is important to quantitatively validate the dynamic response of the models in terms of the input impedance (Z = oscillatory pressure/oscillatory flow). To address this need, the authors developed an improved physical model. Using a computer study, the authors first identified the configuration of lumped parameter elements in a model of the systemic circulation; the result was a good match with human aortic input impedance with a minimum number of elements. Design, construction, and testing of a hydraulic model analogous to the computer model followed. Numeric results showed that a three element model with two resistors and one compliance produced reasonable matching without undue complication. The subsequent analogous hydraulic model included adjustable resistors incorporating a sliding plate to vary the flow area through a porous material and an adjustable compliance consisting of a variable-volume air chamber. The response of the hydraulic model compared favorably with other circulation models.     

Myogenic microvascular responses to change of transmural pressure A mathematical approach

The recently described static and dynamic myogenic responses in the sympathectomized skeletal muscle microvessels to a given transmural pressure (P_T) change applied at different rates (dP_Tldt) (Grände & Mellander 1978), were further analysed in this study with a mathematical approach. The hypothesis that myogenic reactions are triggered by and related to wall tension was also tested. The mathematical model was based on a force–equilibrium in the microvessel wall including passive forces related to vascular transmural pressure, elasticity, and wall–viscosity, and active myogenic forces related to wall tension and its rate of change. Great resemblance was demonstrated between microvascular resistance curves obtained with the model and corresponding curves observed in vivo, indicating that the model quite adequately can describe myogenic microvascular resistance responses to transmural pressure stimuli. The results support the myogenic hypothesis in general and, in particular, the concept of an important rate–sensitivity in myogenic microvascular control and are compatible with the view that myogenic reactions are triggered by and related to change of wall tension. The model, in addition, provided data for certain microvascular variables which are difficult to assess by in vivo observations, e.g. Young's modulus of elasticity, wall tension, its rate of change, and internal vessel radius, and it offered a means to define more precisely the role of physical factors like effects of Poiseuille's and Laplace's laws in vascular resistance regulation.     

Renal autoregulation: evidence for the transmural pressure hypothesis.

Autoregulation of glomerular filtration rate (GFR) was examined during uteral orarterial constriction in anesthetized dogs after renal denervation. GFR was sustaineduntil ureteral pressure greater than 80 mmHg, provided renal arterial pressure exceeded 180 mmHg, but fell at ureteral pressure less than 54 mmHg when arterial pressure averaged 127 plus or minus 5 mmHg; renal blood rose as GFR declined. Ethacrynic acid, saline, or mannitol infusion increased tubular pressure without reducing GFR,but during subsequent ureteral constriction GFR fell at uteral pressure less than 40mmHg. During arterial constriction GFR was maintained at lower arterial pressures in hydropenic than in diuretic dogs. Because of thisdifference in the range of autoregulation, saline infusion increased GFR more in hydropenic than in diuretic dogs except at high arterial pressure. This response to reduced plasma oncotic pressure and the constancy of GFR over a wide range of proximal tubular and arterial pressure indicate constancy of thehydrostatic transmural pressure of glomerular capillaries. Afferent arteriolar resistance is, in addition to a regulation by transmural pressure, perhaps controlled by vascular stretch receptors in the glomeruli.     

Hydromechanical simulation of systemic circulation

A hydromechanical model is developed for the simulation of the arterial systemic circulation. The geometry and elastic properties of arteries, the pulse-rate and stroke volume of the left ventricle, the design of peripheral resistances and the viscosity of the model fluid are approximated to physiological conditions. The parameters, pulse rate, stroke volume, pulse volume, elasticity of arteries, as well as peripheral resistances, are independent variables.     

Myogenic microvascular responses to change of transmural pressure. A mathematical approach.

The recently described static and dynamic myogenic responses in the sympathectomized skeletal muscle microvessels to a given transmural pressure (PT) change applied at different rates (dPT/dt) (Gr?nde & Mellander 1978), were further analysed in this study with a mathematical approach. The hypothesis that myogenic reactions are triggered by and related to wall tension was also tested. The mathematical model was based on a force-equilibrium in the microvessel wall including passive forces related to vascular transmural pressure, elasticity, and wall-viscosity, and active myogenic forces related to wall tension and its rate of change. Great resemblance was demonstrated between microvascular resistance curves obtained with the model and corresponding curves observed in vivo, indicating that the model quite adequately can describe myogenic microvascular resistance responses to transmural pressure stimuli. The results support the myogenic hypothesis in general and, in particular, the concept of an important rate-sensitivity in myogenic microvascular control and are compatible with the view that myogenic reactions are triggered by and related to change of wall tension. The model, in addition, provided data for certain microvascular variables which are difficult to assess by in vivo observations, e.g. Young's modulus of elasticity, wall tension, its rate of change, and internal vessel radius, and it offered a means to define more precisely the role of physical factors like effects of Poiseuille's and Laplace's laws in vascular resistance regulation.     

Validation of a two-compartment model of ventilation/perfusion distribution

Ventilation (V (A)) to perfusion (Q ) heterogeneity (V (A)/Q ) analyses by a two-compartment lung model (2C), utilizing routine gas exchange measurements and a computer solution to account for O(2) and CO(2) measurements, were compared with multiple inert gas elimination technique (MIGET) analyses and a multi-compartment (MC) model. The 2C and MC estimates of V (A)/Q mismatch were obtained in 10 healthy subjects, 43 patients having chronic obstructive pulmonary disease (COPD) and in 14 dog experiments where hemodynamics and acid-base status were manipulated with gas mixtures, fluid loading and tilt-table stressors. MIGET comparisons with 2C were made on 6 patients and 32 measurements in healthy subjects before and after exercise at normoxia and altitude hypoxia. Statistically significant correlations for logarithmic standard deviations of V (A)/Q distributions (SD(V (A)/Q )) were obtained for all 2C comparisons, with similar values between 2C and both other methods in the 1.1-1.5 range, compatible with mild to moderate COPD. 2C tended to overestimate MC and MIGET values at low and underestimate them at high SD(V (A)/Q ) values. SD(V (A)/Q ) weighted by Q agreed better with MC and MIGET estimates in the normal range, whereas SD(V (A)/Q ) weighted by V (A) was closer to MC at higher values because the V (A)-weighted SD(V (A)/Q ) is related to blood-to-gas PCO(2) differences that are elevated in disease, thereby allowing better discrimination. The 2C model accurately described functional V (A)/Q characteristics in 26 normal and bronchoconstricted dogs during non-steady state rebreathing and could be used to quantify the effect of reduced O(2) diffusing capacity in diseased lungs. These comparisons indicate that 2C adequately describes V (A)/Q mismatch and can be useful in clinical or experimental situations where other techniques are not feasible.     

The study of wall deformation and flow distribution with transmural pressure by three-dimensional model of thoracic aorta wall

The sensitivity of shear stress over smooth muscle cells (SMCs) to the deformability of media layer due to pressure is investigated in thoracic aorta wall using three-dimensional simulations. A biphasic, anisotropic model assuming the radius, thickness, and hydraulic conductivity of vessel wall as functions of transmural pressure is employed in numerical simulations. The leakage of interstitial fluid from intima to media layer is only possible through fenestral pores on the internal elastic lamina (IEL). The media layer is assumed a heterogeneous medium containing SMCs embedded in a porous extracellular matrix of elastin, proteoglycan, and collagen fibers. The applicable pressures for the deformation of media layer are varied from 0 to 180 mmHg. The SMCs are cylindrical objects of circular cross section at zero pressure. The cross sectional shape of SMCs changes from circle to ellipse as the media is compressed. The local shear stress over the nearest SMC to the IEL profoundly depends on pressure, SMCs configurations, and the corresponding distance to the IEL. The consideration of various SMC configurations, namely the staggered and square arrays, mimics various physiological conditions that can happen in positioning of an SMC. The results of our simulations show that even the second nearest SMCs to the IEL can significantly change their functions due to high shear stress levels. This is in contrast to earlier studies suggesting the highest vulnerability to shear stress for the innermost layer of SMCs at the intimal-medial interface.     

Effect of pressure on transmural fluid flow in different de-endothelialised arteries

The effect of pressure on filtration across different de-endothelialised arteries has been studied experimentally and the existing theoretical model is validated. Segments of different arteries are excised, de-endotheliaslised and cannulated. Bovine serum albumin Krebs solution is used as perfusate. Transmural water flux is measured by following the movement of an air bubble in a calibrated capillary, which connects the artery to a pressure reservoir; the pressure of which is varied. The hydraulic conductivity L_p is calculated from the flux values. Using available experimental parameters in the case of the thoracic and abdominal aorta, a theoretical model is validated using the experimental results. As the elastic constant for the carotid artery is not available, the theoretical model is used to calculate the elastic constant at different transmural pressures. The values calculated are in the range −4·9×10⁻⁸ to −5·7×10⁻⁹ cm² dyne⁻¹ between 50 and 135 mm Hg. Both theoretical and experimental results show a decrease in L_p values with an increase in transmural pressure for the thoracic and abdominal aorta, whereas a different trend is observed in the case of the carotid artery. The L_p values increase at 90 mm Hg, as compared with 50 mm Hg, and with a further increase in transmural pressure the values decrease.     

Influence of pleural pressure variations on cardiovascular system dynamics: a model study

A mathematical model of the human cardiovascular system (CVS) is used to study the effect of different respiratory manoeuvres on the circulation. The model simulates the normal CVS and the interaction between the heart and the intrathoracic pressure. The vascular system is represented by resistive, capacitive and inertial elements whereas the ventricles are assumed to function according to the time-varying elastance concept based on their transmural pressures. The model predicts that normal inspiratory effeort effects an increase in the venous return, an increase in the pulmonary flow and a slight decrease in the left ventricular stroke volume (LVSV), which represents a decrease in ejection due to the increased LV transmural pressure. A step decrease in pleural pressure to −40 mm Hg, representing the Müller manoeuvre (MM), accentuates these findings, showing a decrease in LVSV in spite of an increase in the LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV) and the LV filling pressure, expressed as the mean left atrial transmural pressure. Simulating intermittent positive pressure ventilation (IPPV) with added positive end expiratory pressure (PEEP) shows an 18·6 per cent decrease in the cardiac output compared with quiet respiration. The calculated results of the model are in good agreement with available experimental data, suggesting that most of these findings may be explained by basic haemodynamic principles in the uncontrolled CVS.     

Comparison of a two-compartment model and distributed models for indicator dilution studies

In nonstationary flow the estimation of the mean flow with an indicator dilution technique can be described by applying a two-compartment model for the system between the injection site and detection site. The aim of this study was to investigate whether the two-compartment approach could be used in experimental situations as encountered in nonsteady blood flow during artificial ventilation. For this reason a two-compartment function was fitted to probability density functions associated with distributed models. The choice of the distributed functions was based on their superiority over other approaches with regard to the representation of the dispersion process of the indicator. Moreover, reference functions enable the practicability of fitting the two-compartment model as a function of the skewness of the curve to be studied. The first passage times (f.p.t.) distribution and the local density random walk (l.d.r.w.) distribution were used as reference functions. Good similarity between the two-compartment curves and the distributed curves was established for the skewness range found in the indicator dilution curves (i.d.c.s.) obtained at the right and left sides of the heart. The closer similarity to the l.d.r.w distribution could be explained theoretically. Moreover, it is concluded that in this skewness range the ratio of the slopes of the ascending and descending limbs at the inflection points of a curve gives an estimate of the time-constant ratio of the compartments of the compartment model.